Capelli, RiccardoLyu, WenpingBolnykh, ViacheslavMeloni, SimoneOlsen, Jogvan Magnus HaugaardRothlisberger, UrsulaParrinello, MicheleCarloni, Paolo2020-09-062020-09-062020-09-062020-08-0610.1021/acs.jpclett.0c00999https://infoscience.epfl.ch/handle/20.500.14299/171436WOS:000562064500081The k(off) values of ligands unbinding to proteins are key parameters for drug discovery. Their predictions based on molecular simulation may under- or overestimate experiment in a system- and/or technique-dependent way. Here we use an established method-infrequent metadynamics, based on the AMBER force field-to compute the k(off )of the ligand iperoxo (in clinical use) targeting the muscarinic receptor M-2. The ligand charges are calculated by either (i) the Amber standard procedure or (ii) B3LYP-DFT. The calculations using (i) turn out not to provide a reasonable estimation of the transition-state free energy. Those using (ii) differ from experiment by 2 orders of magnitude. On the basis of B3LYP DFT QM/MM simulations, we suggest that the observed discrepancy in (ii) arises, at least in part, from the lack of electronic polarization and/or charge transfer in biomolecular force fields. These issues might be present in other systems, such as DNA-protein complexes.Chemistry, PhysicalNanoscience & NanotechnologyMaterials Science, MultidisciplinaryPhysics, Atomic, Molecular & ChemicalChemistryScience & Technology - Other TopicsMaterials SciencePhysicsfree-energyforce-fieldbinding-kineticsproteinefficientdynamicsdeterminantsinhibitormechanismensembletext::journal::journal article::research article